Abiflox®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABYFLOX® (ABYFLOX®)

Composition:

Active substance: levofloxacin;

One film-coated tablet contains levofloxacin hemihydrate equivalent to levofloxacin 250 mg or 500 mg;

Excipients: sodium croscarmellose, microcrystalline cellulose (PH 101), hydroxypropylmethylcellulose, microcrystalline cellulose (PH 102), magnesium stearate; coating Opadry®03B84851: hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 400, talc, iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 250 mg: pink, biconvex, capsule-shaped tablets, film-coated, with a break line on one side of the tablet, marked with "1" on one side and "5" on the other side of the break line, and marked with "T" on the opposite side of the tablet;

Film-coated tablets, 500 mg: pink, biconvex, capsule-shaped tablets, film-coated, with a break line on one side of the tablet, marked with "1" on one side and "4" on the other side of the break line, and marked with "T" on the opposite side of the tablet.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin.

ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin. As an antibacterial agent of the fluoroquinolone group, levofloxacin acts on the DNA gyrase and topoisomerase IV complex.

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (C_max) or the area under the concentration-time curve (AUC) to the minimum inhibitory (suppressive) concentration (MIC (MBC)).

The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones.

Cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed, due to the mechanism of action.

The recommended breakpoints for levofloxacin MIC values, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from intermediate susceptible (moderately resistant) organisms, and intermediate susceptible from resistant organisms, are presented in Table 1 for MIC testing (mg/L).

Table 1

Clinical MIC breakpoints for levofloxacin (20.06.2006)

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 1 mg/l	> 2 mg/l
Pseudomonas spp.	≤ 1 mg/l	> 2 mg/l
Acinetobacter spp.	≤ 1 mg/l	> 2 mg/l
Staphylococcus spp.	≤ 1 mg/l	> 2 mg/l
S. pneumoniae1	≤ 2 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 1 mg/l	> 2 mg/l
H. influenzae, M. catarrhalis2	≤ 1 mg/l	> 1 mg/l
Intermediate values, not species-related3	≤ 1 mg/l	> 2 mg/l

1 The breakpoint between susceptible and intermediate (moderately resistant) strains has been increased from 1 to 2 in order to inhibit the growth of wild-type strains of this microorganism, which demonstrates variability in this parameter. The breakpoints apply to high-dose therapy.

2 Strains with MIC values higher than the breakpoint between susceptible and intermediate (moderately resistant) strains are very rare or have not yet been reported. Identification and antimicrobial susceptibility testing on any such isolate should be repeated, and if the result is confirmed, the isolate should be sent to a reference laboratory.

3 Non-species-specific MIC breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and are independent of the MIC distribution of specific species.

Non-species-specific MIC breakpoints are used only for species for which a species-specific breakpoint has not been defined and are not used for species for which susceptibility testing is not recommended or for which there is insufficient evidence (e.g., Enterococcus, Neisseria, gram-negative anaerobes).

The CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) recommended MIC breakpoints for levofloxacin, which differentiate susceptible from intermediate organisms and intermediate from resistant organisms, are presented in Table 2 for MIC testing (μg/mL) or disk diffusion method (zone diameter [mm] using a 5-μg levofloxacin disk).

Table 2

CLSI Recommended MIC and Disk Diffusion Breakpoints for Levofloxacin (M100-S17, 2007)

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Non-Enterobacteriaceae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Acinetobacter spp.	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Stenotrophomonas maltophilia	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Staphylococcus spp.	≤ 1 µg/mL ≥19 mm	≥ 4 µg/mL ≤ 15 mm
Enterococcus spp.	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
H. influenzae M. catarrhalis1	≤ 2 µg/mL ≥17 mm
Streptococcus pneumoniae	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
Beta-hemolytic Streptococcus	≤ 2 µg/mL ≥17 mm	≥ 8 µg/mL ≤ 13 mm
1 The absence or rare occurrence of resistant strains precludes the definition of any categories other than "susceptible". For isolates yielding results suggestive of the "resistant" category, organism identification and antimicrobial susceptibility test results should be confirmed by a reference laboratory using the CLSI reference dilution method.

Antibacterial spectrum

The prevalence of resistance in selected species may vary geographically and over time. Local information on resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the agent at least questionable for certain types of infections.

Typically susceptible species

Aerobic gram-positive bacteria

Staphylococcus aureus*, methicillin-sensitive, Staphylococcus saprophyticus, Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumoniae*, Streptococcus pyogenes*

Aerobic gram-negative bacteria

Burkholderia cepacia**, Eikenella corrodens, Haemophilus influenzae*, Haemophilus para-influenzae*, Klebsiella oxytoca, Klebsiella pneumoniae*, Moraxella catarrhalis*, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria

Peptostreptococcus

Others

Chlamydophila pneumoniae*, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila*, Mycoplasma pneumoniae*, Mycoplasma hominis, Ureaplasma urealyticum.

Species for which acquired (secondary) resistance may be problematic

Aerobic gram-positive bacteria

Enterococcus faecalis*, Staphylococcus aureus methicillin-resistant*, Staphylococcus coagulase spp.*

Aerobic gram-negative bacteria

Acinetobacter baumannii*, Citrobacter freundii*, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae*, Escherichia coli*, Morganella morganii*, Proteus mirabilis*, Providencia stuartii, Pseudomonas aeruginosa*, Serratia marcescens*

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thetaiotaomicron**, Bacteroides vulgatus**, Clostridium difficile**

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

** Naturally intermediate susceptibility.

Other data

Hospital-acquired infections caused by P. aeruginosa may require combination therapy.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations reached within 1 hour. Absolute bioavailability is approximately 100%.

Food has almost no effect on the absorption of levofloxacin.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. There is virtually no cumulative effect with repeated administration of levofloxacin 500 mg once daily. A slight but predictable cumulative effect occurs after repeated doses of 500 mg twice daily. Steady state is achieved within 3 days.

Tissue and body fluid penetration

Penetration into bronchial mucosa, bronchial secretions, and lung tissue (BSLT)

Maximum concentrations of levofloxacin in bronchial mucosa and bronchial secretions after a single 500 mg oral dose are 8.3 µg/g and 10.8 µg/mL, respectively. These levels are achieved within 1 hour after dosing.

Penetration into lung tissue

Maximum concentration of levofloxacin in lung tissue after a single 500 mg oral dose is approximately 11.3 µg/g, achieved 4–6 hours after administration. Concentrations in lung tissue exceed those in plasma.

Penetration into bladder contents

Maximum concentrations of levofloxacin of 4–6.7 µg/mL in bladder contents are achieved 2–4 hours after dosing, during 3 days of treatment with 500 mg once or twice daily, respectively.

Penetration into cerebrospinal (CSF) fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue

After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue reach 8.7 µg/g, 8.2 µg/g, and 2.0 µg/g at 2, 6, and 24 hours, respectively. The mean prostate/plasma concentration ratio is 1.84.

Urine concentration

Mean urine concentrations 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg of levofloxacin are 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Biotransformation

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose).

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that these routes (oral and intravenous) are interchangeable.

Linearity

Levofloxacin exhibits linear pharmacokinetics in the range of 50–600 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance are decreased, and elimination half-lives are prolonged, as shown in Table 3.

Table 3

Creatinine clearance (mL/min)	< 20	20–40	50–80
Renal clearance (mL/min)	13	26	57
Elimination half-life (hours)	35	27	9

Geriatric Patients

There are no significant differences in the pharmacokinetics of levofloxacin in younger and elderly patients, except for differences related to creatinine clearance.

Gender Differences

Separate analysis in male and female patients has shown minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

Levofloxacin is indicated for the treatment in adults of the following infections caused by microorganisms sensitive to levofloxacin:

• acute bacterial sinusitis;
• acute exacerbation of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• complicated skin and soft tissue infections;
• uncomplicated cystitis;

(when treating the above-mentioned infections, the drug should be used only if other antibacterial agents typically prescribed for initial treatment of these infections cannot be used);

• acute pyelonephritis and complicated urinary tract infections;
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment.

Levofloxacin in this pharmaceutical form (tablets) may be used to complete the course of therapy in patients who have shown clinical improvement during initial treatment with levofloxacin infusion solution.

Official recommendations regarding the appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the drug; epilepsy; tendon damage following previous use of fluoroquinolones; childhood; pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Antacids containing magnesium and aluminium: medicinal products containing iron salts, zinc, or didanosine.

The absorption of levofloxacin is substantially reduced when administered concomitantly with antacids containing magnesium and aluminium, medicinal products containing iron salts, or didanosine (didanosine in a buffered tablet with aluminium or magnesium). Concurrent administration of fluoroquinolones with multivitamins containing zinc results in reduced absorption.

The recommended interval between administration of levofloxacin and the aforementioned medicinal products should be at least 2 hours.

Calcium salts have minimal effect on the absorption of levofloxacin.

Sucralfate

The bioavailability of levofloxacin tablets is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to administer sucralfate 2 hours after levofloxacin (see section "Dosage and administration").

Theophylline, fenbufen, or other similar nonsteroidal anti-inflammatory drugs

No pharmacokinetic interaction between levofloxacin and theophylline has been demonstrated. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, nonsteroidal anti-inflammatory drugs, and other medicinal products that reduce seizure threshold. It is known that levofloxacin concentrations are approximately 13% higher in the presence of fenbufen than when levofloxacin is administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid. This is explained by the fact that both drugs are capable of blocking tubular secretion of levofloxacin. Levofloxacin should be used with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other medicinal products

Calcium carbonate, digoxin, glyburide, and ranitidine do not exhibit clinically significant effects on the pharmacokinetics of levofloxacin when administered concomitantly.

Effect of the drug on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), coagulation test parameters (INR/international normalized ratio) may increase and/or bleeding may occur, which can be severe. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

Levofloxacin, like other fluoroquinolones, should be administered with caution to patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotic medicinal products) (see section "Special precautions for use" ("QT interval prolongation")).

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2; therefore, levofloxacin is not considered to be a CYP1A2 inhibitor.

Other forms of interaction

Food intake

No clinically significant interaction with food has been observed. Levofloxacin tablets may therefore be administered independently of food intake.

Special precautions for use.

The use of the drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with levofloxacin in these patients should only be initiated if there are no alternative treatment options and after careful assessment of benefit/risk ratio.

Methicillin-resistant S. aureus.

In very severe cases of pneumonia caused by pneumococci, levofloxacin may not demonstrate optimal therapeutic effect.

Hospital-acquired infections caused by P. aeruginosa may require combination therapy.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to fluoroquinolones, including levofloxacin; therefore, levofloxacin is not recommended for treatment of infections caused by MRSA, except when microbial susceptibility to levofloxacin has been confirmed.

Levofloxacin may be prescribed for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis when appropriate diagnostic evaluation has been performed.

The most common pathogen in urinary tract infections may be Escherichia coli resistant to levofloxacin, which should be considered when prescribing levofloxacin to patients with urinary tract diseases. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in Escherichia coli should be taken into account.

For the pulmonary form of anthrax, use is based on in vitro susceptibility data for Bacillus anthracis, animal experimental data, and limited human experience. Physicians should refer to national and/or international consensus guidelines for the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems of the body—sometimes multiple systems simultaneously—(including musculoskeletal, nervous, psychiatric, and sensory systems) have been reported. The drug should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Tendinitis and tendon rupture.

Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones and have also been reported several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients who have undergone solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Clostridium difficile-associated disease.

Diarrhea, especially severe, persistent, or bloody diarrhea during or after treatment (including several weeks after treatment) with levofloxacin, may be symptoms of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening, with the most severe form being pseudomembranous colitis. If pseudomembranous colitis is suspected, the drug should be discontinued immediately, and patients should be urgently treated with supportive measures; specific therapy may also be required (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures.

The drug is contraindicated in patients with a history of epilepsy. As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures, particularly those with prior central nervous system (CNS) disorders, concomitant therapy with fenbufen or similar nonsteroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with quinolone antibacterial agents and therefore should receive levofloxacin with caution.

Patients with renal impairment.

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Method of administration and dosage").

Hypersensitivity reactions.

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.

Severe skin reactions.

Severe adverse skin reactions, such as toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens–Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use and may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of these severe skin reactions, and close monitoring should be maintained during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-administration of levofloxacin is contraindicated in patients who have experienced a serious reaction such as SJS, TEN, or DRESS syndrome during prior treatment.

Blood glucose alterations.

As with other quinolones, cases of hypoglycemia have been reported, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glyburide) or insulin. Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported. Hypoglycemic coma has been documented. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

Prevention of photosensitization.

Although photosensitization is very rare with levofloxacin, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) due to the potential for photosensitization during and within 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists.

Due to the potential for increased coagulation test parameters (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), monitoring of coagulation parameters is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, these reactions have progressed to suicidal ideation and self-harming behavior, sometimes even after a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation.

Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• advanced age;
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia);
• concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics). Elderly patients and younger women are more sensitive to drugs that prolong the QT interval. Therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage" ("Elderly patients"), "Overdose", "Adverse reactions").

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician immediately to prevent the development of potentially irreversible conditions.

Hepatobiliary disorders.

Cases of necrotizing hepatitis up to life-threatening liver failure have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal outcomes and the need for respiratory support, have been reported during post-marketing use of fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Adverse reactions", "Ability to affect reaction speed when driving or operating machinery").

Superinfection.

With the use of levofloxacin, particularly prolonged use, the development of opportunistic infections and overgrowth of resistant microorganisms is possible. Appropriate measures should be taken if secondary infection occurs.

Laboratory tests.

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate results using specific methods may be necessary.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological testing of patients with tuberculosis.

Aneurysm/dissection of the aorta.

Epidemiological data suggest an increased risk of aortic aneurysm or dissection with fluoroquinolone use, particularly in elderly patients. Therefore, fluoroquinolone antibiotics should only be used after careful benefit/risk assessment and consideration of alternative treatment options in patients with aortic aneurysm/dissection, patients with a family history of aortic aneurysm, and patients with risk factors or conditions predisposing to aortic aneurysm/dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behçet’s disease, hypertension, and atherosclerosis).

In case of sudden abdominal, chest, or back pain, patients should seek immediate emergency medical assistance.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolones to damage developing joint cartilage, levofloxacin is contraindicated in pregnant and breastfeeding women. If pregnancy occurs during treatment, the patient should inform her physician.

Breastfeeding period. Levofloxacin is contraindicated during breastfeeding. Information on the excretion of levofloxacin into breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage developing joint cartilage, levofloxacin should not be administered to breastfeeding women.

Fertility. Levofloxacin did not cause fertility or reproductive function disorders in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Patients who drive vehicles or operate machinery should be aware of possible adverse nervous system reactions (dizziness, somnolence, confusion, visual and hearing disturbances, motor disturbances, including during walking).

Method of administration and dosage.

The drug should be taken 1 or 2 times daily. The dosage depends on the type and severity of the infection. The duration of treatment depends on the course of the disease. It is recommended to continue treatment with the drug for at least 48–72 hours after body temperature normalization or until microbiological tests confirm eradication of the causative agent.

Tablets should be swallowed whole with sufficient amount of liquid.

The drug may be taken either with food or at another time.

Table 4

Dosage for adult patients with normal renal function (creatinine clearance above 50 ml/min)

Indications	Daily dose	Number of doses per day	Duration of treatment
Acute bacterial sinusitis	500 mg	Once	10–14 days
Exacerbation of chronic obstructive pulmonary disease, including bronchitis	500 mg	Once	7–10 days
Community-acquired pneumonia	500 mg	1–2 times	7–14 days
Acute pyelonephritis	500 mg	Once	7–10 days
Complicated urinary tract infections including pyelonephritis	500 mg	Once	7–14 days
Uncomplicated cystitis	250 mg	Once	3 days
Chronic bacterial prostatitis	500 mg	Once	28 days
Complicated skin and soft tissue infections	500 mg	1–2 times	7–14 days
Pulmonary anthrax	500 mg	Once	8 weeks

Special populations

Table 5

Dosing for patients with impaired renal function (creatinine clearance < 50 ml/min).

	Dosing regimen (depending on the severity of infection and nosological form)
	250 mg/24 hours	500 mg/24 hours	500 mg/12 hours
Creatinine clearance	initial dose – 250 mg	initial dose – 500 mg	initial dose – 500 mg
50–20 mL/min	subsequent – 125 mg/ 24 hours	subsequent – 250 mg/ 24 hours	subsequent – 250 mg/ 12 hours
19–10 mL/min	subsequent – 125 mg/ 48 hours	subsequent – 125 mg/ 24 hours	subsequent – 125 mg/ 12 hours
<10 mL/min (as well as during hemodialysis and CRRT1)	subsequent – 125 mg/ 48 hours	subsequent – 125 mg/ 24 hours	subsequent – 125 mg/ 24 hours

1 After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.

Dosing in elderly patients. If renal function is normal, dose adjustment is not required (see section "Special precautions": Tendinitis and tendon rupture, QT interval prolongation).

Children.

The use of the medicinal product is contraindicated in children (under 18 years of age), as damage to joint cartilage cannot be excluded.

Overdose.

The most important expected symptoms of overdose involve the central nervous system (dizziness, altered consciousness, and seizures); gastrointestinal reactions such as nausea and mucosal erosion. When doses higher than therapeutic are administered, QT interval prolongation occurs. In case of overdose, careful patient monitoring including ECG is required.

Treatment: symptomatic therapy. In case of acute overdose, gastric lavage should be performed. Antacid agents should be used to protect gastric mucosa.

Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. ECG monitoring is necessary due to the potential for QT interval prolongation. There are no specific antidotes.

Adverse Reactions

The frequency of adverse effects was determined using the following criteria: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Within each group, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – fungal infections, including Candida species, proliferation of other resistant microorganisms, disruption of normal intestinal flora, and development of secondary infection.

Blood and lymphatic system disorders: uncommon – leukopenia, eosinophilia; rare – thrombocytopenia, neutropenia; not known – pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: rare – angioedema, hypersensitivity (see section "Special warnings and precautions for use"); not known – anaphylactic/anaphylactoid shock (see section "Special warnings and precautions for use").

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycemia, mainly in diabetic patients (see section "Special warnings and precautions for use"); not known – hyperglycemia, hypoglycemic coma (see section "Special warnings and precautions for use").

Psychiatric disorders*: common – insomnia; uncommon – anxiety, restlessness, fear, confusion, nervousness; rare – psychotic reactions (including hallucinations, paranoia), depression, agitation, abnormal dreams, nightmares; not known – psychotic reactions with self-destructive behaviour, including suicidal ideation or actions (see section "Special warnings and precautions for use").

Nervous system disorders*: common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia (subjective taste disturbance); rare – seizures (see section "Contraindications" and "Special warnings and precautions for use"), paraesthesia; not known – peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (impaired motor coordination), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hypertension.

Eye disorders*: rare – visual disturbances such as blurred vision, unsharp vision (see section "Special warnings and precautions for use"); not known – transient loss of vision, uveitis (see section "Special warnings and precautions for use").

Ear and labyrinth disorders*: uncommon – vertigo; rare – tinnitus; not known – hearing loss, hearing impairment.

Cardiac disorders: rare – tachycardia, palpitations, arterial hypotension; not known – ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on ECG (see sections "Special warnings and precautions for use": QT interval prolongation, and "Overdose").

Respiratory system disorders: uncommon – dyspnea (shortness of breath); not known – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence/bloating, constipation; not known – hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"); pancreatitis.

Endocrine disorders: rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Hepatobiliary disorders: common – increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); uncommon – increased blood bilirubin levels; not known – jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use"); hepatitis.

Skin and subcutaneous tissue disorders: rare – drug rash with eosinophilia and systemic symptoms (DRESS syndrome), localized drug-induced skin rash; uncommon – rash, pruritus, urticaria, hyperhidrosis; not known – toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"); leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*: uncommon – arthralgia, myalgia; rare – tendon disorders (see section "Special warnings and precautions for use"), including tendon inflammation (tendinitis) (e.g., Achilles tendon); muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special warnings and precautions for use");

not known – rhabdomyolysis, tendon rupture (e.g., Achilles tendon: see section "Special warnings and precautions for use"), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders: uncommon – elevated serum creatinine levels;

rare – acute renal failure (e.g., due to interstitial nephritis).

General disorders*: uncommon – asthenia; rare – increased body temperature (pyrexia); not known – pain (including back, chest, and limb pain).

a Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.

b Skin and mucous membrane reactions may sometimes occur even after administration of the first dose.

Other adverse effects associated with administration of fluoroquinolones include:

• Acute attacks of porphyria in patients with porphyria.

*In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, organ systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances).

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 film-coated tablets in a blister; 1 blister per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Aurobindo Pharma Limited.

Manufacturer's address and place of business.

Unit VII, Special Economic Zone, TSIIC, Plot No. S1, Sy. No. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepalli Village, Jedcherla Mandal, Mahabubnagar, 509302, India.